Abstract
YM158 (3-[(4-tert-butylthiazol-2-yl)methoxy]-5′-[3-(4-chlorobenzenesulfonyl) propyl]-2′-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate) antagonizes leukotriene (LT) D4 and thromboxane (TX) A2 receptors. Functional assays in vitro showed that YM158 exhibits competitive dual antagonism of LTD4 and TXA2 receptor-mediated contraction of isolated guinea pig tracheae, with pA2 values of about 8.87 and 8.81, respectively. Its antagonistic activity for the LTD4 receptor was approximately 6.5 times less potent than that of montelukast, and that for the TXA2 receptor was 2.5 times more potent than that of seratrodast. YM158 also inhibited PGD2- and PGF2α-induced tracheal contractions. YM158 showed no antagonism against LTC4-, histamine- or carbachol-induced contractions of guinea pig tracheae. Furthermore, YM158 antagonized the stable TXA2 analog U46619-induced aggregation of both guinea pig and human platelets and inhibited the LTD4-induced contraction of guinea pig ileum. From these results, YM158 appears to be a novel, selective dual antagonist for both LTD4 and TXA2 receptors.
Footnotes
-
Send reprint requests to: Yasuhito Arakida, Inflammation Research Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd. 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
- Abbreviations:
- LT
- leukotriene
- Cys-LTs
- cysteinyl-leukotrienes (LTC4, LTD4 and LTE4)
- TX
- thromboxane
- PG
- prostaglandin
- PRP
- platelet-rich plasma
- PPP
- platelet-poor plasma
- IC50
- concentration causing 50% inhibition
- EC50
- concentration causing 50% effect
- YM158
- (3-[(4-tert-butylthiazol-2-yl)methoxy]-5′-[3-(4-chlorobenzenesulfonyl)propyl-2′-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate)
- Received January 7, 1998.
- Accepted June 17, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
